Liraglutide modulates gut microbiota and reduces NAFLD in obese mice.

Metabolic disorders such as insulin resistance and diabetes are associated with obesity and nonalcoholic fatty liver disease (NAFLD). The aggressive form of a fatty liver disease may progress to cirrhosis and hepatocellular carcinoma. Furthermore, recent studies demonstrated that there is a dysbiosis in the gut microbiota associated with early stages of metabolic disease. Therefore, the identification and repurposing of drugs already used to treat insulin resistance may be an excellent option for other disorders. We evaluated the effect of liraglutide on obesity, NAFLD and gut microbiota modulation in two different animal models of obesity: the ob/ob mice and the high-fat diet (HFD)-fed mice. Liraglutide treatment induced significant weight loss in both obesity models, showed improvements in glycemic parameters and reduced inflammatory cell infiltration in the cecum and the liver. In ob/ob mice, the liraglutide treatment was able to reduce the accumulation of liver fat by 78% and reversed steatosis in the HFD mice. The gut microbiota analysis showed that liraglutide changed the overall composition as well as the relative abundance of weight-relevant phylotypes such as a reduction of Proteobacteria and an increase of Akkermansia muciniphila in the treated HFD group. We show that liraglutide can lead to weight loss and gut microbiota modulations, and is associated with an improvement of NAFLD. Furthermore, by generating a profile of the intestinal microbiota, we compiled a list of potential bacterial targets that may modulate metabolism and induce a metabolic profile that is considered normal or clinically controlled.

Correction: Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.

[This corrects the article DOI: 10.1371/journal.ppat.1005742.].

Features of Recently Transmitted HIV-1 Clade C Viruses that Impact Antibody Recognition: Implications for Active and Passive Immunization.

The development of biomedical interventions to reduce acquisition of HIV-1 infection remains a global priority, however their potential effectiveness is challenged by very high HIV-1 envelope diversity. Two large prophylactic trials in high incidence, clade C epidemic regions in southern Africa are imminent; passive administration of the monoclonal antibody VRC01, and active immunization with a clade C modified RV144-like vaccines. We have created a large representative panel of C clade viruses to enable assessment of antibody responses to vaccines and natural infection in Southern Africa, and we investigated the genotypic and neutralization properties of recently transmitted clade C viruses to determine how viral diversity impacted antibody recognition. We further explore the implications of these findings for the potential effectiveness of these trials. A panel of 200 HIV-1 Envelope pseudoviruses was constructed from clade C viruses collected within the first 100 days following infection. Viruses collected pre-seroconversion were significantly more resistant to serum neutralization compared to post-seroconversion viruses (p = 0.001). Over 13 years of the study as the epidemic matured, HIV-1 diversified (p = 0.0009) and became more neutralization resistant to monoclonal antibodies VRC01, PG9 and 4E10. When tested at therapeutic levels (10ug/ml), VRC01 only neutralized 80% of viruses in the panel, although it did exhibit potent neutralization activity against sensitive viruses (IC50 titres of 0.42 µg/ml). The Gp120 amino acid similarity between the clade C panel and candidate C-clade vaccine protein boosts (Ce1086 and TV1) was 77%, which is 8% more distant than between CRF01_AE viruses and the RV144 CRF01_AE immunogen. Furthermore, two vaccine signature sites, K169 in V2 and I307 in V3, associated with reduced infection risk in RV144, occurred less frequently in clade C panel viruses than in CRF01_AE viruses from Thailand. Increased resistance of pre-seroconversion viruses and evidence of antigenic drift highlights the value of using panels of very recently transmitted viruses and suggests that interventions may need to be modified over time to track the changing epidemic. Furthermore, high divergence such as that observed in the older clade C epidemic in southern Africa may impact vaccine efficacy, although the correlates of infection risk are yet to be defined in the clade C setting. Findings from this study of acute/early clade C viruses will aid vaccine development, and enable identification of new broad and potent antibodies to combat the HIV-1 C-clade epidemic in southern Africa.

Differences in HIV type 1 neutralization breadth in 2 geographically distinct cohorts in Africa.

To investigate whether distinct populations have differing human immunodeficiency virus type 1 (HIV) neutralizing antibody responses, we compared 20 women from Tanzania's HIV Superinfection Study (HISIS) cohort, who were infected multiple HIV subtypes, and 22 women from the Centre for the AIDS Programme of Research in South Africa (CAPRISA) cohort, who were infected exclusively with HIV subtype C. By 2 years after infection, 35% of HISIS subjects developed neutralization breadth, compared with 9% of CAPRISA subjects (P = .0131). Cumulative viral loads between 3 and 12 months were higher in the HISIS group (P = .046) and strongly associated with breadth (P < .0001). While viral load was the strongest predictor, other factors may play a role, as the odds of developing breadth remained higher in HISIS even after correction for viral load.

Supplementation of moist and dehydrated citrus pulp in the diets of sheep artificially and naturally infected with gastrointestinal nematodes on the parasitological parameters and performance.

The inclusion of industrial byproducts such as citrus pulp in the composition of animal diets has been widely recommended due to sustainability aspects and their high level of carbohydrates. Limonene is found in citrus pulp and has been described elsewhere as a major compound of citrus essential oils with excellent anthelmintic activity. The objective of this study was to evaluate the parasitological parameters of lambs artificially infected (Experiment 1) with Haemonchus contortus and naturally infected (Experiment 2) by gastrointestinal nematodes, fed diets with dehydrated citrus pulp or silage of moist orange pulp. Both experiments had three treatments (C: control, DP: diet+dehydrated citrus pulp, and MP: diet+silage of moist orange pulp). The diets were isoproteic (11% crude protein) and the concentrate was corrected every 14 days according to animal weight. Parasitological parameters were evaluated for both experiments each 14 days (body weight, body condition; fecal egg counts-FEC, egg hatch assay-EHA, coproculture, and packed cell volume-PCV). Analysis of variance (GLM of the SAS software) was performed with repeated measures in time, and the means were compared by the Tukey test. Gas chromatography with mass spectrometry was used to detect constituents of dry or moist citrus pulp. Dehydrated citrus pulp had 0.02% essential oil (major compounds were 85.9% limonene and 7.6% valencene). Moist orange pulp contained 1.5% essential oil (major compounds were 65.5% limonene and 31.2% alpha- and gamma-terpineol). In both experiments, the weight gain among the treatments was similar (p>0.05) demonstrating that both moist and dehydrated orange pulp can be used to replace corn kernels to feed infected lambs. The supplementation with orange pulp did not decrease natural or artificial infections of gastrointestinal nematodes according to the FEC results (p>0.05). However, PCV increased from animals fed dehydrated and moist pulp in natural infection (Experiment 2, p<0.05) in comparison with the control group. In addition, the consumption of the dehydrated citrus pulp from animals infected with H. contortus (Experiment 1) caused lower hatching rates after 42 days of consumption (p<0.05), suggesting a tendency to shed fewer eggs to the environment.

Epidemiology of HIV-1 subtypes among men who have sex with men in Cape Town, South Africa.

OBJECTIVE: Early studies in Cape Town identified independent HIV-1 epidemics, with distinct viral subtypes, among men who have sex with men (MSM) and the heterosexual population. However, few recent HIV-1 subtype data are available for MSM in South Africa. We examined HIV-1 subtypes among MSM in Cape Town. DESIGN: Cross-sectional survey. METHODS: Self-identified MSM were recruited from geographically and racially disparate communities across Cape Town. Participants completed behavioral questionnaires and underwent HIV testing. Virus isolated from infected participants underwent complete env gp160 sequencing, and HIV-1 subtypes were assigned through phylogenetic analysis. RESULTS: In total, 194 HIV-infected MSM were enrolled: 67% black African, 24% colored, and 9% white men. More black African men identified as bisexual or heterosexual compared with other races. Overall, 31%-66% of men reported a recent partner of another race. HIV-1 subtypes were confirmed for 143 participants: 81% were subtype C, 14% B, 1% A1, 1% F2, and 3 recombinant viruses. Subtype C virus was associated with black African race (P = 0.003 compared with colored; P < 0.001 compared with white), men who identified as bisexual/heterosexual (P = 0.01), and reported a female sexual partner in the last year (P = 0.02). Compared with previous studies, an increasing prevalence of subtype C virus was noted among white MSM. CONCLUSIONS: This molecular epidemiology study provides novel evidence of sexual network links between the heterosexual and MSM epidemics and between historically racially disparate communities. These findings provide insights into the drivers of HIV epidemics in different population groups and may have implications for prevention strategies.

The association of CD81 polymorphisms with alloimmunization in sickle cell disease.

The goal of the present work was to identify the candidate genetic markers predictive of alloimmunization in sickle cell disease (SCD). Red blood cell (RBC) transfusion is indicated for acute treatment, prevention, and abrogation of some complications of SCD. A well-known consequence of multiple RBC transfusions is alloimmunization. Given that a subset of SCD patients develop multiple RBC allo-/autoantibodies, while others do not in a similar multiple transfusional setting, we investigated a possible genetic basis for alloimmunization. Biomarker(s) which predicts (predict) susceptibility to alloimmunization could identify patients at risk before the onset of a transfusion program and thus may have important implications for clinical management. In addition, such markers could shed light on the mechanism(s) underlying alloimmunization. We genotyped 27 single nucleotide polymorphisms (SNPs) in the CD81, CHRNA10, and ARHG genes in two groups of SCD patients. One group (35) of patients developed alloantibodies, and another (40) had no alloantibodies despite having received multiple transfusions. Two SNPs in the CD81 gene, that encodes molecule involved in the signal modulation of B lymphocytes, show a strong association with alloimmunization. If confirmed in prospective studies with larger cohorts, the two SNPs identified in this retrospective study could serve as predictive biomarkers for alloimmunization.

Submandibular glands and the regulation of gastric proliferation and TGFα distribution during rat postnatal development

Rodent gastric mucosa grows and differentiates during suckling-weaning transition. Among the molecules in rat milk, EGF and TGFβ are important peptides in the control of cell proliferation, and together with TGFα, they are also produced by submandibular glands. We aimed to determine the effect of saliva and milk on epithelial cell proliferation in the stomach of rat pups. We also examined the distribution of TGFα in the gastric mucosa after sialoadenectomy (SIALO) and fasting in order to determine whether this growth factor is affected by the deprivation of molecules derived from saliva and milk. SIALO was performed at 14 days and fasting was induced 3 days later. Cell proliferation was evaluated through metaphasic index and TGFα was detected by immunohistochemistry. We observed that whereas SIALO did not alter cell division, since the metaphasic index (MI) was unchanged, fasting stimulated cell proliferation (P < 0.05). After SIALO and fasting, MI was reduced when compared to the fasted group (P < 0.05). We found that TGFα is distributed along gastric gland and SIALO did not interfere in the localization and number of immunolabeled cells, but fasting increased their density when compared to the control (P < 0.05). The association of SIALO and fasting reduced TGFα immunostaining (P < 0.05). Therefore, during fasting, high MI was parallel to increased TGFα in gastric epithelium, but interestingly, this effect was found only in the presence of submandibular glands. We suggest that during suckling, peptides derived from saliva and milk are important to regulate gastric growth.

EGFR is involved in control of gastric cell proliferation through activation of MAPK and Src signalling pathways in early-weaned rats.

OBJECTIVES: Early weaning (EW) increases proliferation of the gastric epithelium in parallel with higher expression of transforming growth factor alpha and its receptor epidermal growth factor receptor (EGFR). The primary objective of the present study was to examine involvement of EGFR signalling in regulating mucosal cell proliferation during the early weaning period. MATERIALS AND METHODS: Fifteen-day-old rats were split into two groups: suckling (control) and EW, in which pups were separated from the dam. Animals were killed daily until the 18th day, 3 days after onset of treatment. To investigate the role of EGFR in proliferation control, EW pups were injected with AG1478, an EGFR inhibitor; signalling molecules, proliferative indices and cell cycle-related proteins were evaluated. RESULTS: EW increased ERK1/2 and Src phosphorylation at 17 days, but p-Akt levels were unchanged. Moreover, at 17 days, AG1478 administration impaired ERK phosphorylation, whereas p-Src and p-Akt were not altered. AG1478 treatment reduced mitotic and DNA synthesis indices, which were determined on HE-stained and BrdU-labelled sections. Finally, AG1478 injection decreased p21 levels in the gastric mucosa at 17 days, while no changes were detected in p27, cyclin E, CDK2, cyclin D1 and CDK4 concentrations. CONCLUSIONS: EGFR is part of the mechanism that regulates cell proliferation in rat gastric mucosa during early weaning. We suggest that such responses might depend on activation of MAPK and/or Src signalling pathways and regulation of p21 levels.

The Brazilian database on pregnancy in multiple sclerosis.

OBJECTIVES: To report the results from the Brazilian database on multiple sclerosis (MS) and pregnancy. METHODS: Retrospective data from MS patients who became pregnant at any time of their disease were sent to a Brazilian database, using a specific file for this purpose. RESULTS: Data on 128 women (142 pregnancies) from 30 neurologists working in 21 cities in Brazil were collected. Patients' average age at pregnancy was 29.8 years (range 16-42). EDSS at start of pregnancy was 1.5±1.4; and the relapse rate in the year preceding pregnancy was 1.2±1.5. Exposure to medication at any time during pregnancy was high (69.7%): 48.6% to interferon beta; 14.1% to glatiramer acetate; and 7% to other immunomodulatory and immunosuppressive drugs. There was a significant decrease in relapse rate during pregnancy. The prevalence of complications was relatively low, with 4.9% of obstetric and 1.4% neonatal unfavorable outcomes. CONCLUSIONS: Our patients had low degrees of disability, short histories of disease, high drug exposure, and relatively high relapse rate in the year previous to pregnancy. Obstetric and neonatal outcomes were successful in over 90% of our patients.

Recurrent neuromyelitis optica in Brazilian patients: clinical, immunological, and neuroimaging characteristics.

Neuromyelitis optica has not been thoroughly studied in Brazilian patients following the discovery of NMO-IgG and its specific antigen aquaporin-4. In this study we aimed to describe the clinical NMO-IgG immunological status and neuroimaging characteristics of recurrent neuromyelitis optica in a series Brazilian patients. We undertook a retrospective study of 28 patients with recurrent neuromyelitis optica, according to 1999 Wingerchuk's diagnostic criteria. Data on NMO-IgG status, clinical features, and MRI findings were analyzed. Three men and 25 women were evaluated. Median age at onset of disease was 26 years (range 7-55); median time of follow-up was 7 years (range 2-14). The mean time elapsed between the first and the second attack was 17 months (median 8.5; range 2-88). NMO-IgG was detected in 18 patients (64.3%). Four patients died due to respiratory failure. Most patients presented with cervical (36%) and cervical-thoracic myelitis (46.4%). Holocord lesion was the most common pattern of involvement (50%) on the axial plane. We did not find a statistical association between myelitis extension and NMO-IgG result. Our series of Brazilian patients showed a younger age of onset than previously reported. In our series, in contrast to previous reports, there was no correlation between the extension of myelitis and NMO-IgG positivity.

Conserved positive selection signals in gp41 across multiple subtypes and difference in selection signals detectable in gp41 sequences sampled during acute and chronic HIV-1 subtype C infection.

BACKGROUND: The high diversity of HIV variants driving the global AIDS epidemic has caused many to doubt whether an effective vaccine against the virus is possible. However, by identifying the selective forces that are driving the ongoing diversification of HIV and characterising their genetic consequences, it may be possible to design vaccines that pre-empt some of the virus' more common evasion tactics. One component of such vaccines might be the envelope protein, gp41. Besides being targeted by both the humoral and cellular arms of the immune system this protein mediates fusion between viral and target cell membranes and is likely to be a primary determinant of HIV transmissibility. RESULTS: Using recombination aware analysis tools we compared site specific signals of selection in gp41 sequences from different HIV-1 M subtypes and circulating recombinant forms and identified twelve sites evolving under positive selection across multiple major HIV-1 lineages. To identify evidence of selection operating during transmission our analysis included two matched datasets sampled from patients with acute or chronic subtype C infections. We identified six gp41 sites apparently evolving under different selection pressures during acute and chronic HIV-1 infections. These sites mostly fell within functional gp41 domains, with one site located within the epitope recognised by the broadly neutralizing antibody, 4E10. CONCLUSION: Whereas these six sites are potentially determinants of fitness and are therefore good candidate targets for subtype-C specific vaccines, the twelve sites evolving under diversifying selection across multiple subtypes might make good candidate targets for broadly protective vaccines.

Chronic hyperglycaemia increases TGFbeta2 signaling and the expression of extracellular matrix proteins in the rat parotid gland.

The majority of the oral manifestations of diabetes mellitus are secondary to a reduced salivary flow, whose causes are still poorly understood. In the kidney, diabetes complications involve increased Transforming Growth Factor beta (TGFbeta) production and the thickening of basement membrane in small vessels. By using immunohistochemistry and western blotting, we studied the expression and signaling of TGFbeta and the distribution of extracellular matrix (ECM) proteins: laminin, fibronectin, collagens III, IV and V in the parotid gland of control and diabetic rats, 30 and 60 days after streptozotocin injection (D30 and D60). At D30, there was an important increase of laminin whereas fibronectin and collagen V were moderately augmented. At D60, an additional increase of all ECM proteins was observed. TGFbeta1 expression was not affected at any time. In contrast, TGFbeta2 levels were significantly higher at D30, concomitant with increased TGFbeta receptor II (TbetaRII), phosphorylated Smads 2 and 3 (pSmads 2-3) and Latent TGFbeta Binding Protein 1 (LTBP1). At D60, TGFbeta2 and TbetaRII were still increased, whereas phosphorylation of Smads was markedly decreased, and LTBP1 returned to control levels. In the control groups, TGFbeta2 labeling was localized preferentially in ductal cells, whereas at D30 and D60 the staining was also observed in acinar cells. The same pattern of distribution was observed for pSmads 2-3 at D30, especially in nuclei. At D60, labeling was weak and dispersed throughout the cytoplasm. These data suggest that hyperglycaemia increases the deposition of ECM proteins in the rat parotid gland, possibly through augmentation of TGFbeta2 expression and signaling.

Differential distribution of transforming growth factor beta and receptors in the hyper or hypoproliferative gastric mucosa of developing and adult rats.

Transforming growth factor beta (TGFbeta) isoforms are known for their antiproliferative effect on epithelial cells in vitro, but the role of each isoform in vivo is poorly understood, mainly when non-pathological conditions are considered. We correlated the presence and distribution of isoforms and receptors to physiological changes in gastric cell proliferation in developing and adult rats. We used fasting to induce either the hyper (14-day-old pups) or hypoproliferation (60-day-old rats) of the gastric epithelium. In 14-d-old pups fasting reduced only TGFbeta3 labelling in the gland. Conversely, in 60-d-old rats there was an increase of TGFbeta1 and TGFbeta3 immunolabelled cells. Receptors were detected at both ages. Therefore, the changes induced by fasting in the constitutive TGFbeta expression can be correlated to the differential epithelial proliferation in the stomach of developing and adult rats. These results suggest that one of the functional roles of TGFbeta in vivo is to locally regulate cell proliferation.

Ileal VIP submucous neurons: confocal study of the area enlargement induced by myenteric denervation in weanling rats.

Vasoactive Intestinal Peptide (VIP) neurons are maturing during suckling and weaning periods and the neuropeptide VIP is thought to be neurotrophic during ontogenesis. We have previously demonstrated that suckling rats with myenteric ablation have significantly higher mitotic index and an increase on villus height and crypt depth 15 days after treatment. In the current study, we measured the area of VIP neurons of submucous plexus in the ileum of weanling rats, in which myenteric neurons were ablated by serosal application of benzalkonium chloride (BAC). The area of VIP immunoreactive cell bodies, reconstructed under confocal microscope, was significantly increased in response to denervation. This result suggests that the myenteric plexus may have an inhibitory role over submucous plexus in the normal intestine. The enhanced production of VIP may be correlated with the increased epithelial proliferation induced by denervation in a critical period of life, from suckling to weaning time.

Serotonin in the nervous system of the head region of the land planarian Bipalium kewense.

The presence and distribution of serotonin (5-hydroxytryptamine, or 5-HT) in the head region of the land planarian Bipalium kewense has been investigated by an indirect immunofluorescence technique combined with confocal scanning laser microscopy (CSLM), and also by immunogold labeling at ultrastructural level. Serotonin immunoreactivity (IR) was restricted to elements of the nervous system, such as the cerebral ganglion, and the peripheral nerve net. Most of 5-HT-immunoreactive neurons are at the periphery of the brain; they were identified as unipolar, bipolar, and multipolar neurons. The ultrastructural results using immunogold labeling confirm the location of 5-HT within electron-dense vesicles (50-120 nm in diameter), clustered both in the cell bodies and in their processes. The intense 5-HT-IR herein demonstrated for B. kewense adds new data to the poorly studied nervous system of land planarians.

Localization of luteinizing-hormone releasing hormone binding sites in the gastric mucosa of suckling rats.

Luteinizing-hormone releasing hormone (LHRH) is a hypothalamic and milk-borne hormone that inhibits the cell proliferation of gastric epithelium in developing rats, although the mechanism of such action is unknown. We investigated the presence of binding sites for LHRH in the stomach of suckling rats after the injection of the hormone. Immunofluorescence at the confocal microscopy level revealed that LHRH binds to gastric cells, being particularly abundant over the gland. Different fluorescent lectins were used to identify gastric cell types and determine which were labeled by the hormone. Colocalization studies in these double-labeling experiments showed that LHRH staining colocalizes with parietal cells, suggesting the presence of binding sites in these cells. The three-dimensional (3-D) reconstruction of isolated parietal cells revealed the localization of the signal, which appears to be in the membrane of the canalicular region. These results suggest that there are binding sites for LHRH in the gastric epithelium, specifically in parietal cells, and they might play a role in the control of cell proliferation during suckling.

Streptozotocin-induced diabetes duration is important to determine changes in the number and basophily of myenteric neurons.

The aim of present study was to evaluate the number and basophily of cell bodies of myenteric neurons in the ileum of rats with diabetes mellitus induced by streptozotocin. Four groups of rats were used: diabetes was induced in two (D) whereas the other two worked as controls (N). Animals were sacrificed six (6N, 6D) or nineteen (19N, 19D) weeks after diabetes induction. A segment of the terminal portion of the ileum of each rat was obtained and stained with Giemsa's solution, for whole-mount preparation studies. Forty fields were analyzed in each animal, and the number and basophily intensity of cell bodies were recorded. After counting, the following mean numbers of neurons/mm2 were obtained: 6N=593.1 +/- 95.75, 6D=639.1 +/- 130.8, 19N=580.1 +/- 175.6 and 19D=402.0 +/- 144.8. The analysis of basophily shown that highest frequency of neurons with weak/intermediary basophily was verified in 6D group (55.3%), whereas the groups 6N, 19N e 19D presented 38%, 36% e 40% respectively. The statistical analysis showed that a long period is necessary to decrease the number of neurons/mm2 in the rat ileum after diabetes induction, and that there was a reduction in basophily intensity in diabetic rats after 6 weeks of treatment, and such cells do not recover after a longer period (19 weeks).

Cell proliferation and death in the gastric epithelium of developing rats after glucocorticoid treatments.

Glucocorticoids take part in the intense morphofunctional modifications that occur in the gastric mucosa during fetal and postnatal development. Two studies were designed to evaluate corticoids role in gastric cell proliferation and apoptosis in developing rats: in vivo, using suckling animals; in vitro, using gastric explants obtained from 20-day fetuses. These explants were cultured in DMEM/F12 medium treated or not with 50 ng/ml of corticosterone; after 22 hr, vincristine was added to the medium for 2 hr to block mitosis. The metaphasic index decreased significantly after the 24-hr treatment (controls: 1.52 +/- 0.53; treated: 0.40 +/- 0.21) and apoptotic cells were visualized under light and electron microscopy. Fifteen-day-old rats were treated with hydrocortisone (25 mg/Kg) for 3 days, and injected with BrDU (100 mg/Kg) 1 hr before sacrifice on the 18th day. BrDu-labeled and non-labeled cells were counted to determine the labeling index of epithelial cells. As apoptotic cells are rapidly eliminated, other animals were treated for only 2-3 hr. Sections were investigated for the presence of apoptotic cells, using morphological criteria and TUNEL labeling. Hydrocortisone significantly reduced the labeling index (controls: 15.6 +/- 1.6 vs. treated: 11.7 +/- 1.1), besides altering the body weight gain. Hydrocortisone treatment doubled the number of apoptotic cells after 2 hr, and quadruplicated it after 3 hr. The results demonstrated that glucocorticoids inhibit cell proliferation in the gastric epithelium of fetuses and suckling rats and increase apoptotic rates, suggesting the exit from cell cycle.

Early weaning and prolonged nursing induce changes in cell proliferation in the gastric epithelium of developing rats.

Food deprivation stimulates cell proliferation in the gastric epithelium of suckling, but not weanling rats. This study was designed to investigate the role of diet on proliferation in developing animals, using early weaning and prolonged nursing models. Rat pups were subjected to these dietary conditions at d 15 and were killed 3 or 7 d afterwards. One day before killing, half of pups were deprived of food. Body weights were recorded. After mitosis blockade, the histologic sections of the stomach were used for the evaluation of cell proliferation and methapasic cell distribution along the gland, and for the measurement of mucosa thickness. Body weight was impaired at 18 d by early weaning and at 22 d by prolonged nursing. Food restriction promoted a 10-15% weight loss regardless of dietary conditions. At 18 d, food deprivation inhibited cell division (P: < 0.01) and reduced the thickness of the mucosa (P: < 0.05) in rats that were weaned early. At 22 d, only the thickness of the mucosa was different between the groups that were subjected to early weaning and prolonged nursing (P: < 0.05), regardless of feeding state. The frequency of dividing cells along the gland was affected by early weaning in 18- and 22-d-old rats. These results suggest the following: 1) food deprivation effects are dependent on dietary condition at 18 d because different proliferative responses were achieved after early weaning and prolonged nursing; 2) the lack of changes after dietary manipulation in 22-d-old rats indicates a nonresponsive period during postnatal development. We conclude that milk is a modulatory factor for cell proliferation in the gastric mucosa of rats.